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Opioid modulation of neural encoding of motivation and reward

阿片类药物对动机和奖励神经编码的调节

基本信息

批准号：
9026648
负责人：
KRISTEN A KEEFE
金额：
$ 37.25万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-03 至 2018-02-28
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Our long-term goal is to understand the contribution of neural reward circuits to control of food intake during normal consumption as well as in pathologies that incorporate binge eating. We are specifically interested in how opioid signaling within reward circuits, particularly in the shell of the nucleus accumbens (sNAcc), mediates binge-like food intake. Stimulation of mu opioid receptors (MORs) in the sNAcc induces voracious feeding and sNAcc opioid receptor and ligand expression is altered in rat models of diet-induced binge eating. However, the mechanisms through which sNAcc MOR stimulation causes hyperphagia, and how diet-induced changes in this circuit contribute to binge eating behavior, remain poorly understood. In previous studies, we characterized two firing patterns in sNAcc neurons that we hypothesize play important and distinct roles in processing of taste hedonics and controlling appetitive food-seeking behavior. Our data suggests that the first of these firing patterns encodes palatability, while the second serves to permissively gate food-seeking behavior (and subsequent consumption) through a disinhibition mechanism. In the present proposal, we will test the hypothesis that distinct effects of sNAcc MOR stimulation on these firing patterns act to increase palatability-induced hyperphagia and food-seeking appetitive behaviors through signaling in segregated anatomical pathways. We further hypothesize that diet-induced binge eating arises specifically through sensitization of opioid signaling in the neural pathway mediating appetitive food-seeking, rather than through changes in pathways processing palatability. To address these hypotheses, we will use a combination of in vivo electrophysiological and pharmacological approaches to characterize the effects of sNAcc MOR manipulations on firing in efferent targets of the sNAcc. We will investigate interactions between the sNAcc and target regions using simultaneous electrode array recordings and cross-correlation techniques to characterize functional connectivity between these regions. Finally, we will characterize electrophysiological and pharmacological changes occurring in this circuit in a rat model of diet-induced binge eating. We anticipate that these experiments will provide important insights into the mechanisms underlying hyperphagia caused by sNAcc MOR stimulation and diet-induced binge eating. These experiments will lead to greater understanding of neural-circuit mechanisms underlying compulsive food intake, and are thus highly relevant in developing novel therapeutic interventions for eating disorders such as bulimia nervosa.

描述（由申请人提供）：我们的长期目标是了解神经奖励回路在正常消费期间以及在暴饮暴食的病理过程中控制食物摄入的贡献。我们特别感兴趣的是奖赏回路中的阿片类信号传导，特别是伏隔核（sNAcc）的外壳中的阿片类信号传导如何介导暴饮暴食般的食物摄入。刺激 sNAcc 中的 mu 阿片受体 (MOR) 会诱导贪婪的进食，并且在饮食诱导暴食的大鼠模型中，sNAcc 阿片受体和配体的表达发生改变。然而，sNAcc MOR 刺激引起食欲亢进的机制，以及饮食引起的该回路变化如何导致暴食行为，仍然知之甚少。在之前的研究中，我们描述了 sNAcc 神经元的两种放电模式，我们假设它们在味觉享乐的处理和控制食欲的食物寻找行为中发挥着重要而独特的作用。我们的数据表明，第一种放电模式编码适口性，而第二种放电模式则通过去抑制机制来允许限制食物寻找行为（以及随后的消费）。在本提案中，我们将测试以下假设：sNAcc MOR 刺激对这些放电模式的独特影响通过隔离解剖通路中的信号传导来增加适口性引起的食欲亢进和寻求食物的食欲行为。我们进一步假设，饮食引起的暴饮暴食是通过调节食欲食物寻找的神经通路中阿片类信号传导的敏化而产生的，而不是通过处理适口性的通路的变化而产生的。为了解决这些假设，我们将结合使用体内电生理学和药理学方法来表征 sNAcc MOR 操作对 sNAcc 传出靶标放电的影响。我们将使用同步电极阵列记录和互相关技术来研究 sNAcc 和目标区域之间的相互作用，以表征这些区域之间的功能连接。最后，我们将在饮食引起的暴饮暴食的大鼠模型中描述该回路中发生的电生理和药理学变化。我们预计这些实验将为 sNAcc MOR 刺激和饮食引起的暴饮暴食引起的暴食机制提供重要的见解。这些实验将有助于更好地了解强迫性食物摄入背后的神经回路机制，因此对于开发针对神经性贪食症等饮食失调的新型治疗干预措施具有高度相关性。